Systems and methods for treating autonomic instability and medical conditions associated therewith

ABSTRACT

One aspect of the present disclosure relates to a closed-loop therapy system for treating autonomic instability or a medical condition associated therewith in a subject. The therapy delivery system can include a sensing component, a delivery component, and a controller. The sensing component can be configured to detect at least one physiological parameter associated with autonomic instability or a medical condition associated therewith. The delivery component can be configured for implantation on or about an autonomic nervous tissue target or a spinal nervous tissue target. The controller can be configured to automatically coordinate operation of the sensing and delivery components. The controller can also be configured to deliver an electrical signal to the delivery component to modulate activity at the autonomic nervous tissue target or a spinal nervous tissue target and effectively treat autonomic instability or a medical condition associated therewith.

RELATED APPLICATION

This application is a continuation-in-part application of of PCTApplication No. PCT/US2014/022386, filed on Mar. 10, 2014, which claimspriority to U.S. Provisional Patent Application Ser. No. 61/776,099,filed Mar. 11, 2013, the entirety of all applications is herebyincorporated by reference for all purposes.

TECHNICAL FIELD

The present disclosure relates generally to neuromodulatory devices,systems and methods, and more particularly to devices, systems, andmethods for treating autonomic instability and medical conditionsassociated therewith.

BACKGROUND

Dysfunction of the autonomic nervous system (ANS) is known asdysautonomia. The ANS regulates unconscious body functions, includingheart rate, blood pressure, temperature regulation, gastrointestinalsecretion, and metabolic and endocrine responses to stress, such as the“fight or flight” syndrome. As regulating these functions involvesvarious and multiple organ systems, dysfunctions of the ANS encompassvarious and multiple disorders. Autonomic dysfunction or instability isa common condition that influences many areas of medicine, such asneurological disorders.

SUMMARY

The present disclosure relates generally to neuromodulatory devices,systems and methods, and more particularly to devices, systems, andmethods for treating autonomic instability or a medical conditionassociated therewith.

One aspect of the present disclosure relates to a closed-loop therapysystem for treating autonomic instability or a medical conditionassociated therewith in a subject. The therapy delivery system caninclude a sensing component, a delivery component, and a controller. Thesensing component can be configured to detect at least one physiologicalparameter associated with autonomic instability or a medical conditionassociated therewith. The delivery component can be configured forimplantation on or about an autonomic nervous tissue target or a spinalnervous tissue target. The controller can be configured to automaticallycoordinate operation of the sensing and delivery components. Thecontroller can also be configured to deliver an electrical signal to thedelivery component to modulate activity at the autonomic nervous tissuetarget or a spinal nervous tissue target and effectively treat autonomicinstability or the medical condition associated therewith.

Another aspect of the present disclosure relates to a closed-looptherapy delivery system for treating autonomic instability or a medicalcondition associated therewith in a subject. The therapy delivery systemcan consist of a sensing component, a delivery component, and acontroller. The sensing component can be configured to detect at leastone physiological parameter associated with autonomic instability or themedical condition associated therewith. The delivery component can beconfigured for implantation on or about a cervicothoracic ganglion. Thecontroller can be configured to automatically coordinate operation ofthe sensing and delivery components. The controller can be configured todeliver an electrical signal to the delivery component to modulateactivity of the cervicothoracic ganglion and effectively treat theautonomic instability or the medical condition associated therewith.

Another aspect of the present disclosure relates to a method fortreating autonomic instability or a medical condition associatedtherewith in a subject. One step of the method can include placing atherapy delivery device into electrical communication with an autonomicnervous tissue target or a spinal nervous tissue target associated withautonomic instability or a medical condition associated therewith. Next,the therapy delivery device can be activated to deliver an electricalsignal to the autonomic nervous tissue target or a spinal nervous tissuetarget to effectively treat autonomic instability or the medicalcondition associated therewith in the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present disclosure will becomeapparent to those skilled in the art to which the present disclosurerelates upon reading the following description with reference to theaccompanying drawings, in which:

FIG. 1 is schematic illustration showing the cervical and upper thoracicportions of the sympathetic nerve chain and the spinal cord;

FIG. 2 is a schematic illustration of a human spinal cord and associatedvertebrae;

FIG. 3 is a schematic illustration showing a closed-loop therapydelivery system for treating autonomic instability or a medicalcondition associated therewith configured according to one aspect of thepresent disclosure;

FIG. 4 is a process flow diagram illustrating a method for treatingautonomic instability or a medical condition associated therewithaccording to another aspect of the present disclosure;

FIG. 5 is a schematic illustration showing the closed-loop therapydelivery system of FIG. 3 implanted in a subject;

FIG. 6 is a schematic illustration showing a transcutaneousneuromodulatory device constructed in accordance with another aspect ofthe present disclosure;

FIGS. 7A-B are schematic illustrations showing alternativetranscutaneous neuromodulatory devices constructed in accordance withother aspects of the present disclosure; and

FIG. 8 is a schematic illustration showing the closed-loop therapydelivery system in FIG. 3 implanted in a human subject.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the present disclosure pertains.

In the context of the present disclosure, the term “autonomic nervoustissue” can refer to any tissues of the sympathetic nervous system (SNS)or the parasympathetic nervous system (PNS) including, but not limitedto, neurons, axons, fibers, tracts, nerves, plexus, afferent plexusfibers, efferent plexus fibers, ganglia, pre-ganglionic fibers,post-ganglionic fibers, afferents, efferents, and combinations thereof.

As used herein, the terms “epidural space” or “spinal epidural space”can refer to an area in the interval between the dural sheath and thewall of the spinal canal. In some instances, at least a portion of atherapy delivery device or a therapy delivery system may be implanted inthe epidural space.

As used herein, the term “subdural” can refer to the space between thedura mater and arachnoid membrane. In some instances, at least a portionof a therapy delivery device or a therapy delivery system may beimplanted in the subdural space.

As used herein, the phrase “spinal nervous tissue” can refer to nerves,neurons, neuroglial cells, glial cells, neuronal accessory cells, nerveroots, nerve fibers, nerve rootlets, parts of nerves, nerve bundles,mixed nerves, sensory fibers, motor fibers, dorsal root, ventral root,dorsal root ganglion, spinal ganglion, ventral motor root, generalsomatic afferent fibers, general visceral afferent fibers, generalsomatic efferent fibers, general visceral efferent fibers, grey matter,white matter, the dorsal column, the lateral column, and/or the ventralcolumn associated with the spinal cord.

As used herein, the term “subject” can be used interchangeably with theterm “patient” and refer to any warm-blooded organism including, but notlimited to, human beings, pigs, rats, mice, dogs, goats, sheep, horses,monkeys, apes, farm animals, livestock, rabbits, cattle, etc.

As used herein, the terms “modulate” or “modulating” with reference toan autonomic nervous tissue target or spinal nervous tissue target canrefer to causing a change in neuronal activity, chemistry and/ormetabolism. The change can refer to an increase, decrease, or even achange in a pattern of neuronal activity. The terms may refer to eitherexcitatory or inhibitory stimulation, or a combination thereof, and maybe at least electrical, magnetic, ultrasound, optical, chemical, or acombination of two or more of these. The terms “modulate” or“modulating” can also be used to refer to a masking, altering,overriding, or restoring of neuronal activity.

As used herein, the terms “substantially blocked” or “substantiallyblock” when used with reference to nervous tissue activity can refer toa complete (e.g., 100%) or partial inhibition (e.g., less than 100%,such as about 90%, about 80%, about 70%, about 60%, or less than about50%) of nerve conduction through the nervous tissue.

As used herein, the term “activity” when used with reference toautonomic or spinal nervous tissue can, in some instances, refer to theability of a nerve, neuron, or fiber to conduct, propagate, and/orgenerate an action potential. In other instances, the term can refer tothe frequency at which a nerve or neuron is conducting, propagating,and/or generating one or more action potentials at a given moment intime. In further instances, the term can refer to the frequency at whicha nerve or neuron is conducting, propagating, and/or generating one ormore action potentials over a given period of time (e.g., seconds,minutes, hours, days, etc.).

As used herein, the term “electrical communication” can refer to theability of an electric field generated by an electrode or electrodearray to be transferred, or to have a neuromodulatory effect, withinand/or on autonomic or spinal nervous tissue.

As used herein, the terms “autonomic instability” or “autonomicdysfunction can refer to any abnormal fluctuation in sympathetic and/orparasympathetic tone above or below a normal or baseline (e.g., healthy)level. Such abnormal fluctuation can be chronic (e.g., months, years,etc.) or acute (e.g., hours, days, etc.).

As used herein, the terms “medical condition associated with autonomicinstability” or “medical condition associated with autonomicdysfunction” can refer to any disease, disorder, sign, or symptom thatis associated with, or results at least in part from, autonomicinstability or dysfunction. In some instances, a medical conditionassociated with autonomic instability or dysfunction can includeneurodegenerative disease, such as Parkinson's disease, multiple systemsatrophy, other atypical parkinsonian syndromes, neuropathy,inflammatory/autoimmune disease, demyelinating disorders, such asGuillian Barre Syndrome, paraneoplastic syndromes, infectious etiologies(e.g., botulism), Chagas, addictions (e.g., alcoholism), mitochondrialdisorders, spinal cord injury, brain injury, concussions, other trauma,complex regional pain syndrome, heavy metal toxicity, other toxicities,amyloidosis, porphyria, and also inherited disorders such as Fabry'sdisease and Hereditary Sensory Autonomic Neuropathy syndromes. In otherinstances, a medical condition associated with autonomic instability ordysfunction can be characterized by one or more signs or symptoms, suchas problems with blood pressure regulation (e.g., orthostatichypotension and hypertension), cardiac arrhythmia (e.g.,tachycardia/bradycardia), dysfunctional gastrointestinal motility (e.g.,reflux, gastroparesis), genitourinary trouble (e.g., urinaryincontinence, overactive bladder, erectile dysfunction), impaired sweatresponse (e.g., hyperhidrosis or anhidrosis), dysfunctional temperatureregulation, and also changes in salivary production (e.g., sialorrhea),trouble with ambulation due to lightheadedness/near syncope, recurrentsyncope, severe reflux, trouble with swallowing, difficulty clearingoral secretion, reoccurring aspiration, poor gastrointestinalabsorption, reoccurring bowel obstructions, unexplained fevers, constantsweating, hot/cold intolerance, frequent urination, urinaryincontinence, and recurrent urinary tract infections.

As used herein, the terms “treat” or “treating” can refer totherapeutically regulating, preventing, improving, alleviating thesymptoms of, and/or reducing the effects of autonomic instability or amedical condition associated therewith. As such, treatment also includessituations where autonomic instability or a medical condition associatedtherewith, or at least symptoms associated therewith, is completelyinhibited, e.g., prevented from happening or stopped (e.g., terminated)such that the subject no longer suffers from autonomic instability orthe medical condition associated therewith, or at least the symptomsthat characterize autonomic instability or the medical conditionassociated therewith. In some instances, the terms can refer toimproving or normalizing at least one function of an organ or organtissue affected by an imbalanced sympathetic and/or parasympatheticinput.

As used herein, the term “in communication” can refer to at least aportion of a therapy delivery device or therapy delivery system beingadjacent, in the general vicinity, in close proximity, or directly nextto and/or directly on an autonomic nervous tissue target or spinal nervetarget associated with autonomic instability or a medical conditionassociated therewith. In some instances, the term can mean that at leasta portion of a therapy delivery device or therapy delivery system is “incommunication” with an autonomic nervous tissue target or a spinalnervous tissue target if application of a therapy signal (e.g., anelectrical and/or chemical signal) thereto results in a modulation ofneuronal activity to elicit a desired response, such as modulation of asign or symptom associated with autonomic instability or a medicalcondition associated therewith.

As used herein, the singular forms “a,” “an” and “the” can include theplural forms as well, unless the context clearly indicates otherwise. Itwill be further understood that the terms “comprises” and/or“comprising,” as used herein, can specify the presence of statedfeatures, steps, operations, elements, and/or components, but do notpreclude the presence or addition of one or more other features, steps,operations, elements, components, and/or groups thereof.

As used herein, the term “and/or” can include any and all combinationsof one or more of the associated listed items.

As used herein, phrases such as “between X and Y” and “between about Xand Y” can be interpreted to include X and Y.

As used herein, phrases such as “between about X and Y” can mean“between about X and about Y.”

As used herein, phrases such as “from about X to Y” can mean “from aboutX to about Y.”

It will be understood that when an element is referred to as being “on,”“attached” to, “connected” to, “coupled” with, “contacting,” etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on,” “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “directly adjacent” another feature may have portionsthat overlap or underlie the adjacent feature, whereas a structure orfeature that is disposed “adjacent” another feature may not haveportions that overlap or underlie the adjacent feature.

Spatially relative terms, such as “under,” “below,” “lower,” “over,”“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms can encompass different orientations of adevice in use or operation, in addition to the orientation depicted inthe figures. For example, if a device in the figures is inverted,elements described as “under” or “beneath” other elements or featureswould then be oriented “over” the other elements or features.

It will be understood that, although the terms “first,” “second,” etc.may be used herein to describe various elements, these elements shouldnot be limited by these terms. These terms are only used to distinguishone element from another. Thus, a “first” element discussed below couldalso be termed a “second” element without departing from the teachingsof the present disclosure. The sequence of operations (or steps) is notlimited to the order presented in the claims or figures unlessspecifically indicated otherwise.

Overview

A brief discussion of the pertinent neurophysiology is provided toassist the reader with understanding certain aspects of the presentdisclosure.

The Autonomic Nervous System (ANS)

The nervous system is divided into the somatic nervous system and theANS. In general, the somatic nervous system controls organs undervoluntary control (e.g., skeletal muscles) and the ANS controlsindividual organ function and homeostasis. For the most part, the ANS isnot subject to voluntary control. The ANS is also commonly referred toas the visceral or automatic system.

The ANS can be viewed as a “real-time” regulator of physiologicalfunctions which extracts features from the environment and, based onthat information, allocates an organism's internal resources to performphysiological functions for the benefit of the organism, e.g., respondsto environment conditions in a manner that is advantageous to theorganism. The ANS acts through a balance of its two components: thesympathetic nervous system (SNS) and the parasympathetic nervous system(PNS), which are two anatomically and functionally distinct systems.Both of these systems include myelinated preganglionic fibers which makesynaptic connections with unmyelinated postganglionic fibers, and it isthese fibers which then innervate the effector structure. These synapsesusually occur in clusters called ganglia. Most organs are innervated byfibers from both divisions of the ANS, and the influence is usuallyopposing (e.g., the vagus nerve slows the heart, while the sympatheticnerves increase its rate and contractility), although it may be parallel(e.g., as in the case of the salivary glands). Each of these is brieflyreviewed below.

The SNS is the part of the ANS comprising nerve fibers that leave thespinal cord in the thoracic and lumbar regions and supply viscera andblood vessels by way of a chain of sympathetic ganglia (also referred toas the sympathetic chain, sympathetic trunk or the gangliated cord)running on each side of the spinal column, which communicate with thecentral nervous system via a branch to a corresponding spinal nerve. Thesympathetic trunks extend from the base of the skull to the coccyx. Thecephalic end of each is continued upward through the carotid canal intothe skull, and forms a plexus on the internal carotid artery; the caudalends of the trunks converge and end in a single ganglion, the ganglionimpar, placed in front of the coccyx. As partly shown in FIG. 1, theganglia of each trunk are distinguished as cervical, thoracic, lumbar,and sacral and, except in the neck, they closely correspond in number tothe vertebrae.

The SNS controls a variety of autonomic functions including, but notlimited to, control of movement and secretions from viscera andmonitoring their physiological state, stimulation of the sympatheticsystem inducing, e.g., the contraction of gut sphincters, heart muscleand the muscle of artery walls, and the relaxation of gut smooth muscleand the circular muscles of the iris. The chief neurotransmitter in theSNS is adrenaline, which is liberated in the heart, visceral muscle,glands and internal vessels, with acetylcholine acting as aneurotransmitter at ganglionic synapses and at sympathetic terminals inskin and skeletal muscles. The actions of the SNS tend to beantagonistic to those of the PNS.

The neurotransmitter released by the post-ganglionic neurons isnonadrenaline (also called norepinephrine). The action of noradrenalineon a particular structure, such as a gland or muscle, is excitatory insome cases and inhibitory in others. At excitatory terminals, ATP may bereleased along with noradrenaline. Activation of the SNS may becharacterized as general because a single pre-ganglionic neuron usuallysynapses with many post-ganglionic neurons, and the release ofadrenaline from the adrenal medulla into the blood ensures that all thecells of the body will be exposed to sympathetic stimulation even if nopost-ganglionic neurons reach them directly.

The PNS is the part of the ANS controlling a variety of autonomicfunctions including, but not limited to, involuntary muscular movementof blood vessels and gut and glandular secretions from eye, salivaryglands, bladder, rectum and genital organs. The vagus nerve is part ofthe PNS. Parasympathetic nerve fibers are contained within the last fivecranial nerves and the last three spinal nerves and terminate atparasympathetic ganglia near or in the organ they supply. The actions ofthe PNS are broadly antagonistic to those of the SNS lowering bloodpressure, slowing heartbeat, stimulating the process of digestion etc.The chief neurotransmitter in the PNS is acetylcholine. Neurons of theparasympathetic nervous system emerge from the brainstem as part of theCranial nerves III, VII, IX and X (vagus nerve) and also from the sacralregion of the spinal cord via Sacral nerves. Because of these origins,the PNS is often referred to as the “craniosacral outflow”.

In the PNS, both pre- and post-ganglionic neurons are cholinergic (i.e.,they utilize the neurotransmitter acetylcholine). Unlike adrenaline andnoradrenaline, which the body takes around 90 minutes to metabolize,acetylcholine is rapidly broken down after release by the enzymecholinesterase. As a result the effects are relatively brief incomparison to the SNS.

Each pre-ganglionic parasympathetic neuron synapses with just a fewpost-ganglionic neurons, which are located near, or in, the effectororgan, a muscle or gland. As noted above, the primary neurotransmitterin the PNS is acetylcholine such that acetylcholine is theneurotransmitter at all the pre- and many of the post-ganglionic neuronsof the PNS. Some of the post-ganglionic neurons, however, release nitricoxide as their neurotransmitter.

The Central Nervous System (CNS)

The spinal cord (FIG. 2) is part of the CNS, which extends caudally andis protected by the bony structures of the vertebral column. It iscovered by the three membranes of the CNS, i.e., the dura mater,arachnoid and the innermost pia mater. In most adult mammals, itoccupies only the upper two-thirds of the vertebral canal as the growthof the bones composing the vertebral column is proportionally more rapidthan that of the spinal cord. According to its rostrocaudal location,the spinal cord can be divided into four parts: cervical; thoracic;lumbar; and sacral. Two of these are marked by an upper (cervical) and alower (lumbar) enlargement.

Alongside the median sagittal plane, the anterior and the posteriormedian fissures divide the cord into two symmetrical portions, which areconnected by the transverse anterior and posterior commissures. Oneither side of the cord the anterior lateral and posterior lateralfissures represent the points where the ventral and dorsal rootlets(later roots) emerge from the cord to form the spinal nerves. Unlike thebrain, in the spinal cord the grey matter is surrounded by the whitematter at its circumference. The white matter is conventionally dividedinto the dorsal, dorsolateral, lateral, ventral and ventrolateralfuniculi.

Each half of the spinal grey matter is crescent-shaped, although thearrangement of the grey matter and its proportion to the white mattervaries at different rostrocaudal levels. The grey matter can be dividedinto the dorsal horn, intermediate grey, ventral horn, and acentromedial region surrounding the central canal (central grey matter).The white matter gradually ceases towards the end of the spinal cord andthe grey matter blends into a single mass (conus terminalis) whereparallel spinal roots form the so-called cauda equine.

The present disclosure relates generally to neuromodulatory devices,systems and methods, and more particularly to devices, systems, andmethods for treating autonomic instability or a medical conditionassociated therewith. The ANS regulates the intrinsic function andbalance of each body organ and maintains homeostasis and balance of thecardiovascular, hormonal, and sleep systems. Neuromodulation of the ANSis a precise, controlled, and highly targeted approach to influence andimpact the function and dysfunction in humans. Neuromodulation accordingto the present disclosure can improve the function, activate, inhibit,modulate, and impact the intrinsic autonomic and circadian neural tone,as well as normalize or regulate the function andsympathetic/parasympathetic output to the various body systems (e.g.,cardiovascular, gastrointestinal, and body homeostasis), which areimpacted in autonomic instability and dysfunction. As described indetail below, the present disclosure advantageously provides, in someinstances, devices, systems, and methods for uncoupling dysfunctionalnerve signals from the brain to the ANS (as well as ascending signalsinto the CNS), as well as dysfunctional nerve signals from the ANS toperipheral tissues (e.g., cardiac, gastric, vascular, immunological, andother related tissues/organs) to effectively normalize or regulate theANS (e.g., the SNS). By employing such devices, systems and methods, thepresent disclosure can treat autonomic instability and medicalconditions associated therewith.

Therapy Delivery Devices and Systems

In one aspect, the present disclosure includes various therapy deliverydevices (not shown) and related systems configured to treat autonomicinstability and medical conditions associated therewith in a subject. Insome instances, therapy delivery devices that may be used to practicethe present disclosure may be positioned directly on or in an autonomicnervous tissue target or spinal nervous tissue target. In otherinstances, therapy delivery devices that may be used to practice thepresent disclosure can be positioned below the skin of a subject, butnot directly on or in an autonomic nervous tissue target or spinalnervous tissue target. In further instances, therapy delivery devicesthat may be used to practice the present disclosure can compriseexternal devices, e.g., positioned in a lumen adjacent an autonomicnervous tissue target or spinal nervous tissue target. In still furtherinstances, therapy delivery devices used to practice the presentdisclosure can comprise an external device, e.g., positioned on the skinof a subject adjacent an autonomic nervous tissue target or spinalnervous tissue target. Therapy delivery devices can be temporarily orpermanently implanted within, on, or otherwise associated with a subjectsuffering from, afflicted by, or suspected of having autonomicinstability or a medical condition associated therewith.

Therapy delivery devices of the present disclosure can be configured todeliver various types of therapy signals to an autonomic nervous tissuetarget or spinal nervous tissue target. For example, therapy deliverydevices of the present disclosure can be configured to deliver onlyelectrical energy, only magnetic energy, only a pharmacological orbiological agent, or a combination thereof. In one example, therapydelivery devices of the present disclosure can comprise at least oneelectrode and an integral or remote power source, which is in electricalcommunication with the one or more electrodes and configured to produceone or more electrical signals (or pulses). In another example, therapydelivery devices can include a pharmacological or biological agentreservoir, a pump, and a fluid dispensing mechanism. Non-limitingexamples of pharmacological and biological agents can include chemicalcompounds, drugs (e.g., prazosin, clonidine), nucleic acids,polypeptides, stem cells, toxins (e.g., botulinum), as well as variousenergy forms, such as ultrasound, radiofrequency (continuous or pulsed),magnetic waves, cryotherapy, and the like. In yet another example,therapy delivery devices can be configured to deliver magnetic nervestimulation with desired field focality and depth of penetration. Oneskilled in the art will appreciate that combinations of the therapydelivery devices above configurations are also included within the scopeof the present disclosure.

In some instances, therapy delivery devices can comprise a stimulator(or inhibitor), such as an electrode, a controller or programmer, andone or more connectors (e.g., leads) for connecting the stimulating (orinhibiting) device to the controller. In one example, which is describedin further detail below, the present disclosure can include aclosed-loop therapy delivery system 10 (FIG. 2) for treating autonomicinstability or a medical condition associated therewith. As shown inFIG. 2, the therapy delivery system 10 can include a sensing component12, a delivery component 14, a controller 16, and a power source 18.Each of the sensing component 12, delivery component 14, controller 16,and power source 18 can be in electrical communication with one another(e.g., via a physical connection, such as a lead, or a wireless link).In some instances, each of the sensing and delivery components 12 and 14can comprise an electrode. In other instances, the delivery component 14can comprise a coil configured to deliver magnetic stimulation. Infurther describing representative electrodes, which are described in thesingular, it will be apparent that more than one electrode may be usedas part of a therapy delivery device. Accordingly, the description of arepresentative electrode suitable for use in the therapy deliverydevices of the present disclosure is applicable to other electrodes thatmay be employed.

An electrode can be controllable to provide output signals that may bevaried in voltage, frequency, pulse-width, current and intensity. Theelectrode can also provide both positive and negative current flow fromthe electrode and/or is capable of stopping current flow from theelectrode and/or changing the direction of current flow from theelectrode. In some instances, therapy delivery devices can include anelectrode that is controllable, i.e., in regards to producing positiveand negative current flow from the electrode, stopping current flow fromthe electrode, changing direction of current flow from the electrode,and the like. In other instances, the electrode has the capacity forvariable output, linear output and short pulse-width, as well as pairedpulses and various waveforms (e.g., sine wave, square wave, and thelike).

The power source 18 can comprise a battery or generator, such as a pulsegenerator that is operatively connected to an electrode via thecontroller 16. The power source 18 can be configured to generate anelectrical signal or signals. In one example, the power source 18 caninclude a battery that is rechargeable by inductive coupling. The powersource 18 may be positioned in any suitable location, such as adjacentthe electrode (e.g., implanted adjacent the electrode), or a remote sitein or on the subject's body or away from the subject's body in a remotelocation. An electrode may be connected to the remotely positioned powersource 18 using wires, e.g., which may be implanted at a site remotefrom the electrode(s) or positioned outside the subject's body. In oneexample, an implantable power source 18 analogous to a cardiac pacemakermay be used.

The controller 16 can be configured to control the pulse waveform, thesignal pulse width, the signal pulse frequency, the signal pulse phase,the signal pulse polarity, the signal pulse amplitude, the signal pulseintensity, the signal pulse duration, and combinations thereof of anelectrical signal. In other instances, the controller 16 can beconfigured to control delivery of magnetic energy or stimulation to thedelivery component 14. The controller 16 may be used to convey a varietyof currents and voltages to one or more electrodes and thereby modulatethe activity of a target sympathetic nervous tissue. The controller 16may be used to control numerous electrodes independently or in variouscombinations as needed to provide stimulation or inhibition of nerveactivity. In some instances, an electrode may be employed that includesits own power source, e.g., which is capable of obtaining sufficientpower for operation from surrounding tissues in the subject's body, orwhich may be powered by bringing a power source 18 external to thesubject's body into contact with the subject's skin, or which mayinclude an integral power source.

The electrical signal (or signals) delivered by the controller 16 to thedelivery component 14 may be constant, varying and/or modulated withrespect to the current, voltage, pulse-width, cycle, frequency,amplitude, and so forth. For example, a current may range from about0.001 to about 1000 microampere (mA) and, more specifically, from about0.1 to about 100 mA, and even more specifically from about 0.1 to about25 mA. Similarly, the voltage may range from about 0.1 millivolt toabout 25 volts, or about 0.5 to about 4000 Hz, with a pulse-width ofabout 5 microseconds to about 5000 microseconds, and more specifically,from about 10 to about 1000 microseconds. The frequency may range fromabout 5 Hz to about 25,000 Hz. In one example, the electrical signal canbe oscillatory. The type of stimulation may vary and involve differentwaveforms known to the skilled artisan. For example, the stimulation maybe based on the H waveform found in nerve signals (i.e., HoffmanReflex). In another example, different forms of interferentialstimulation may be used.

To increase nerve activity in a portion of the ANS, for example, voltageor intensity may range from about 1 millivolt to about 1 volt or more,e.g., 0.1 to about 50 mA or volts (e.g., from about 0.2 volts to about20 volts), and the frequency may range from about 1 Hz to about 10,000Hz, e.g., about 1 Hz to about 1000 Hz (e.g., from about 2 Hz to about100 Hz). In some instances, pure DC and/or AC voltages may be employed.The pulse-width may range from about 1 microsecond to about 10,000microseconds or more, e.g., from about 10 microseconds to about 2000microseconds (e.g., from about 15 microseconds to about 1000microseconds). The electrical signal may be applied for at least about 1millisecond or more, e.g., about 1 second (e.g., about several seconds).In some instances, stimulation may be applied for as long as about 1minute or more, e.g., about several minutes or more (e.g., about 30minutes or more).

To decrease activity in a portion of the ANS, for example, voltage orintensity may range from about 1 millivolt to about 1 volt or more,e.g., 0.1 to about 50 mA or volts (e.g., from about 0.2 s volt to about20 volts), and the frequency may range from about 1 Hz to about 2500 Hz,e.g., about 50 Hz to about 2500 Hz. In one example, an electrical signalcan have a frequency range of about 10,000 Hz or greater (e.g., highfrequency stimulation) to effectively block nerve conduction, and morespecifically from about 10,000 Hz to about 25,000 Hz. In some instances,pure DC and/or AC voltages may be employed. The pulse-width may rangefrom about 1 microseconds to about 10,000 microseconds or more, e.g.,from about 10 microseconds to about 2000 microseconds (e.g., from about15 microseconds to about 1000 microseconds). The electrical signal maybe applied for at least about 1 millisecond or more, e.g., about 1second (e.g., about several seconds). In some instances, the electricalenergy may be applied for as long as about 1 minute or more, e.g., aboutseveral minutes or more (e.g., about 30 minutes or more may be used).

The electrode may be mono-polar, bipolar or multi-polar. To minimize therisk of an immune response triggered by the subject against the therapydelivery device, and also to minimize damage thereto (e.g., corrosionfrom other biological fluids, etc.), the electrode (and any wires andoptional housing materials) can be made of inert materials, such assilicon, metal, plastic and the like. In one example, a therapy deliverydevice can include a multi-polar electrode having about four exposedcontacts (e.g., cylindrical contacts).

As discussed above, the controller 16 (or a programmer) may beassociated with a therapy delivery device. The controller 16 caninclude, for example, one or more microprocessors under the control of asuitable software program. Other components of a controller 16, such asan analog-to-digital converter, etc., will be apparent to those of skillin the art. In some instances, the controller 16 can be configured torecord and store data indicative of the intrinsic autonomic tone oractivity in the subject. Therefore, the controller 16 can be configuredto apply one or more electrical signals to the delivery component 14when the intrinsic autonomic tone or activity of a subject increases ordecreases above a certain threshold value (or range of values), such asa normal or baseline level.

Therapy delivery devices can be pre-programmed with desired stimulationparameters. Stimulation parameters can be controllable so that anelectrical signal may be remotely modulated to desired settings withoutremoval of the electrode from its target position. Remote control may beperformed, e.g., using conventional telemetry with an implanted powersource 18, an implanted radiofrequency receiver coupled to an externaltransmitter, and the like. In some instances, some or all parameters ofthe electrode may be controllable by the subject, e.g., withoutsupervision by a physician. In other instances, some or all parametersof the electrode may be automatically controllable by a controller 16.

In one example, the therapy delivery device can be configured forpercutaneous placement or implantation. In this instance, the therapydelivery device can comprise one or more implantable electrodes shapedor configured, for example, as a wire, a rod, a filament, a ribbon, acord, a tube, a formed wire, a flat strip, or a combination thereof. Inone example, one or more of the electrodes can comprise a laminotomyelectrode array. Laminotomy electrodes, for example, generally have aflat paddle configuration and typically possess a plurality ofelectrodes (e.g., 2, 3, 4 or more) arranged on the paddle. Thearrangement of electrodes on the paddle may be in rows and columns,staggered, spaced, circular, or any other arrangement that will positionthe electrodes for optimal delivery of electrical energy. The one ormore implantable electrodes may be controlled individually, in series,in parallel, or any other manner desired. Once implanted, theimplantable electrode(s) may be held in position using any method knownto the skilled artisan, such as stitches, epoxy, tape, glue, sutures, ora combination thereof.

In another example, the therapy delivery device can be configured forintravascular or intraluminal placement or implantation. In someinstances, a therapy delivery device configured for intravascular orintraluminal placement or implantation can be configured in an identicalor similar manner as the expandable electrode disclosed in U.S. patentapplication Ser. No. 11/641,331 to Greenberg et al. (hereinafter, “the'331 application”). In one example, the therapy delivery device can beconfigured for intravascular or intraluminal placement or implantationat an implantation site that is adjacent, or directly adjacent, anautonomic nervous tissue target or spinal nervous tissue target.

In yet another example, the therapy delivery device can be configuredfor transcutaneous neuromodulation. In some instances, transcutaneousneuromodulation can include positioning a delivery component (e.g., anelectrode or magnetic coil) on a skin surface so that a therapy signal(e.g., an electrical signal or magnetic field) can be delivered to anautonomic nervous tissue target or spinal nervous tissue target.Transcutaneous neuromodulation can additionally include partiallytranscutaneous methods (e.g., using a fine, needle-like electrode topierce the epidermis). In other instances, a surface electrode (orelectrodes) or magnetic coil can be placed into electrical contact withan autonomic nervous tissue target or spinal nervous tissue targetassociated with autonomic instability or a medical condition associatedtherewith. Non-limiting examples of transcutaneous neuromodulationdevices that may be used for treating autonomic instability or a medicalcondition associated therewith are discussed below.

In one example, an electrical signal used for transcutaneousneuromodulation may be constant, varying and/or modulated with respectto the current, voltage, pulse-width, cycle, frequency, amplitude, andso forth (e.g., the current may be between about 1 to 100 microampere),about 10 V (average), about 1 to about 1000 Hz or more, with apulse-width of about 250 to about 500 microseconds.

In another example, the present disclosure can include a therapydelivery device or system configured for transcutaneous neuromodulationusing magnetic stimulation. A magnetic stimulation device or system cangenerally include a pulse generator (e.g., a high current pulsegenerator) and a stimulating coil capable of producing magnetic pulseswith desired field strengths. Other components of a magnetic stimulationdevice can include transformers, capacitors, microprocessors, safetyinterlocks, electronic switches, and the like. In operation, thedischarge current flowing through the stimulating coil can generate thedesired magnetic field or lines of force. As the lines of force cutthrough tissue (e.g., neural tissue), a current is generated in thattissue. If the induced current is of sufficient amplitude and durationsuch that the cell membrane is depolarized, nervous tissue will bestimulated in the same manner as conventional electrical stimulation. Itis therefore worth noting that a magnetic field is simply the means bywhich an electrical current is generated within the nervous tissue, andthat it is the electrical current, and not the magnetic field, whichcauses the depolarization of the cell membrane and thus stimulation ofthe target nervous tissue. Thus, in some instances, advantages ofmagnetic over electrical stimulation can include: reduced or sometimesno pain; access to nervous tissue covered by poorly conductivestructures; and stimulation of nervous tissues lying deeper in the bodywithout requiring invasive techniques or very high energy pulses.

Therapy delivery devices can be part of an open- or closed-loop system.In an open-loop system, for example, a physician or subject may, at anytime, manually or by the use of pumps, motorized elements, etc., adjusttreatment parameters, such as pulse amplitude, pulse-width, pulsefrequency, duty cycle, dosage amount, type of pharmacological orbiological agent, etc. Alternatively, in a closed-loop system 10 (asdiscussed above), treatment parameters (e.g., electrical signals) may beautomatically adjusted in response to a sensed physiological parameteror a related symptom or sign indicative of the extent and/or presence ofautonomic instability or a medical condition associated therewith. In aclosed-loop feedback system 10, a sensing component 12 can comprise asensor (not shown in detail) that senses a physiological parameterassociated with autonomic instability or a medical condition associatedtherewith can be utilized. More detailed descriptions of sensors thatmay be employed in closed-loop systems, as well as other examples ofsensors and feedback control techniques that may be employed as part ofthe present disclosure are disclosed in U.S. Pat. No. 5,716,377. One ormore sensing components 12 can be implanted on or in any tissue or organof a subject. For example, a sensing component 12 can be implanted in oron a component of the ANS, such as nerves, ganglia, afferents orefferents, or the spinal cord. Alternatively or additionally, a sensingcomponent 12 can be implanted on or in a body organ and/or an anatomicalconnection thereof.

It should be appreciated that implementing a therapy delivery device aspart of a closed-loop system can include placing or implanting a therapydelivery device on or within a subject at an autonomic nervous tissuetarget or spinal nervous tissue target, sensing a physiologicalparameter associated with autonomic instability or a medical conditionassociated therewith, and then activating the therapy delivery device toapply an electrical signal to adjust application of the electricalsignal, such as adjusting the stimulation parameters as describedherein, to the autonomic nervous tissue target or spinal nervous tissuetarget in response to the sensor signal. In some instances, suchphysiological parameters can include any characteristic, sign, symptom,or function associated with autonomic instability or a medical conditionassociated therewith, such as a chemical moiety or nerve activity (e.g.,electrical activity). Examples of such chemical moieties and nerveactivities can include the activity of autonomic ganglia (or anautonomic ganglion), the activity of a spinal cord segment or spinalnervous tissue associated therewith, protein concentrations,electrochemical gradients, hormones (e.g., cortisol), neuroendocrinemarkers, such as corticosterone, norepinephrine and melatonin,electrolytes, laboratory values, vital signs (e.g., blood pressure),markers of locomotor activity, cardiac markers (e.g., EKG RR intervals),or other signs and biomarkers associated with autonomic instability or amedical condition associated therewith.

Methods

Another aspect of the present disclosure includes a method for treatingautonomic instability or a medical condition associated therewith in asubject. In general, methods of the present disclosure can include thesteps of: providing a therapy delivery device; placing the therapydelivery device into electrical communication with an autonomic nervoustissue target or spinal nervous tissue target associated with autonomicinstability or a medical condition associated therewith; and activatingthe therapy delivery device to deliver a therapy signal (e.g., anelectrical signal or magnetic field) to the autonomic nervous tissuetarget or spinal nervous tissue target to effectively treat autonomicinstability or the medical condition associated therewith. Subjectstreatable by the present disclosure can, in some instances, be diagnosedwith (or suspected of having) autonomic instability or a medicalcondition associated therewith as well as one or more related orunrelated medical conditions. Non-limiting examples of medicalconditions that can be co-treated by the methods of the presentdisclosure can include substance abuse, sleep deprivation or sleepdisorders, psychiatric disturbances or diseases, impulse controldisorders, cardiovascular disease, metabolic disorders (e.g., diabetes),and major depressive episodes.

In some instances, the step of placing a therapy delivery device intoelectrical communication with an autonomic nervous tissue target orspinal nervous tissue target can entail different surgical and/ormedical techniques depending, for example, upon the target tissue. Insome instances, a therapy delivery device can be surgically placed intoelectrical communication with an autonomic nervous tissue target orspinal nervous tissue target via a percutaneous or endoscopic route. Inother instances, a therapy delivery device can be placed into electricalcommunication with an autonomic nervous tissue target or spinal nervoustissue target via an intravascular or intraluminal route. In furtherinstances, a therapy delivery device can be placed into electricalcommunication with an autonomic nervous tissue target or spinal nervoustissue target via a transcutaneous approach.

Examples of autonomic nervous tissue targets into which a therapydelivery device may be placed into electrical communication with caninclude, but are not limited to, any tissues of the SNS or the PNS. Insome instances, autonomic nervous tissue targets into which a therapydelivery device may be placed into electrical communication with caninclude a sympathetic chain ganglion, an efferent of a sympathetic chainganglion, or an afferent of a sympathetic chain ganglion. In otherinstances, the sympathetic chain ganglion can be a cervical sympatheticganglion, a thoracic sympathetic ganglion, or a stellate ganglion.Examples of cervical sympathetic ganglia can include an upper cervicalsympathetic ganglion, a middle cervical sympathetic ganglion, or a lowercervical sympathetic ganglion. Examples of thoracic sympathetic gangliacan include a T1 sympathetic ganglia, a T2 sympathetic ganglia, a T3sympathetic ganglia, a T4 sympathetic ganglia, a T6 sympathetic ganglia,or a T7 sympathetic ganglia.

Examples of spinal nervous tissue targets into which a therapy deliverydevice may be placed into electrical communication with can include, butare not limited to, a C1, C2, C3, C4, C5, C6, C7, or C8 spinal cordsegment or spinal nervous tissue associated therewith, a T1, T2, T3, T4,T5, T6, T7, T8, T9, T10, T11, or T12 spinal cord segment or spinalnervous tissue associated therewith, a L1, L2, L3, L4, or L5 spinal cordsegment or spinal nervous tissue associated therewith, or a S1, S2, S3,S4, or S5 spinal cord segment or spinal nervous tissue associatedtherewith.

After placing the therapy delivery device, the therapy delivery devicecan be activated to deliver a therapy signal (e.g., an electrical signalor magnetic field) to the autonomic nervous tissue target or spinalnervous tissue target. In some instances, delivery of a therapy signalto the autonomic nervous tissue target or spinal nervous tissue targetcan prevent a sign and/or symptom associated with autonomic instabilityor a medical condition associated therewith from either increasing ordecreasing (as compared to a control or baseline). In other instances,delivery of a therapy signal to the autonomic nervous tissue target orspinal nervous tissue target can cause a sign and/or symptom associatedwith autonomic instability or a medical condition associated therewithto decrease (as compared to a control or baseline). The therapy deliverydevice can be activated at the onset of an episode (e.g., the onset of asign and/or symptom) associated with autonomic instability or a medicalcondition associated therewith or, alternatively, the therapy deliverydevice can be activated continuously or intermittently to reduce oreliminate the frequency of such episode(s).

Delivery of the electrical signal to the autonomic nervous tissue targetor spinal nervous tissue target can affect central motor output, nerveconduction, neurotransmitter release, synaptic transmission, and/orreceptor activation at the target tissue(s). For example, the ANS may beelectrically modulated to alter, shift, or change sympathetic and/orparasympathetic activity from a first state to a second state, where thesecond state is characterized by a decrease in sympathetic and/orparasympathetic activity relative to the first state. As discussedabove, delivery of an electrical signal to the autonomic nervous tissuetarget or spinal nervous tissue target can, in some instances,substantially block activity of the autonomic nervous tissue target orspinal nervous tissue target. In other instances, delivery of anelectrical signal to the autonomic nervous tissue target or spinalnervous tissue target can achieve a complete nerve conduction block ofautonomic nervous tissue target or spinal nervous tissue target for adesired period of time. In other instances, delivery of an electricalsignal to the autonomic nervous tissue target or spinal nervous tissuetarget can achieve a partial block of the autonomic nervous tissuetarget or spinal nervous tissue target for a period of time sufficientto decrease sympathetic and/or parasympathetic nerve activity. Infurther instances, delivery of an electrical signal to the autonomicnervous tissue target or spinal nervous tissue target can increasesympathetic tone (e.g., from a hyposypmathetic state) to a normal orbaseline level. The degree to which sympathetic and/or parasympatheticactivity is decreased or increased can be titrated by one skilled in theart depending, for example, upon the nature and severity of autonomicinstability or a medical condition associated therewith.

In another aspect, the present disclosure can include a method 20 (FIG.4) for treating autonomic instability or a medical condition associatedtherewith in a subject. One step of the method 20 can include providinga therapy delivery device (Step 22). Alternatively, Step 22 can includeproviding a closed-loop therapy delivery system. Examples of suitabletherapy delivery devices (and systems) are described above and furtherillustrated below. At Step 24, the therapy delivery device (or system)can be placed into electrical communication with an autonomic nervoustissue target or spinal nervous tissue target associated with autonomicinstability or a medical condition associated therewith (e.g., aneurological or neurodegenerative disorder). In some instances, thetherapy delivery device can be placed in direct electrical contact withthe autonomic nervous tissue target or spinal nervous tissue target.“Direct electrical contact” can mean that the therapy delivery device(or system) is placed on or in the autonomic nervous tissue target orspinal nervous tissue target. In other instances, “direct electricalcontact” can mean that the therapy delivery device (or system) islocated adjacent or directly adjacent (but not in physical contact with)the autonomic nervous tissue target or spinal nervous tissue target suchthat delivery of a therapy signal (e.g., an electrical signal or amagnetic field) can modulate a function, activity, and/or characteristicof the autonomic nervous tissue target or spinal nervous tissue target.

After placing the therapy delivery device (or system) into directelectrical communication with the autonomic nervous tissue target orspinal nervous tissue target, the therapy delivery device (or system)can be activated to deliver the therapy signal to the autonomic nervoustissue target or spinal nervous tissue target (Step 26). The therapysignal can be delivered in an amount and for a time sufficient toeffectively treat autonomic instability or a medical conditionassociated therewith. In one example, electrical energy can be deliveredto the stellate ganglion by an electrode or electrode array that isplaced directly on or in the stellate ganglion. In some instances,autonomic instability or a medical condition associated therewith may becaused by hyposympathetic activity. In such instances, it may bedesirable to deliver continuous stimulation to the stellate ganglion toincrease sympathetic activity in the subject so that the sympathetictone of the subject (or the sympathetic tone of a particular organ ortissue) improves (e.g., to a normal level).

One example of the method 20 is illustrated in FIG. 5. At Step 22, themethod 20 can include providing a closed-loop therapy system 10 asdescribed above. The closed-loop therapy system 10 can be configured forpercutaneous implantation in the subject. As shown in FIG. 5, the system10 can be implanted in the subject so that the delivery component 14 andthe sensing component 12 are in direct electrical contact with thestellate ganglion and the middle cervical ganglion, respectively.Additionally, the system 10 can be implanted so that the controller 16and the power source 18 are secured at the same or differentsubcutaneous locations.

Once the system 10 is implanted (Step 24), the sensing component 12 candetect electrical activity in the middle cervical ganglion, which may beindicative of intrinsic sympathetic tone in the subject. The detectedlevel(s) of electrical activity can then be relayed to the controller16, which determines if the detected level(s) is/are within a normal orabnormal range or level. Where the detected level(s) is/are within anabnormal range (e.g., at an elevated level as compared to a control orbaseline), the controller 16 can cause the power source 18 to deliver anelectrical signal to the delivery component 14. Stimulation parametersof the electrical signal as described herein can also be modulated. Theelectrical signal is then delivered to the stellate ganglion to modulateactivity therein (Step 26). While the electrical signal(s) is/are beingdelivered to the stellate ganglion, the sensing component 12 cancontinue to detect the level of electrical activity within the middlecervical ganglion (Step 28). When the level of electrical activity inthe middle cervical ganglion is equal, or about equal to, a normal orbaseline level, the controller 16 can cease delivery of the electricalsignal(s) to the delivery component 14. By continuously orintermittently monitoring the intrinsic sympathetic tone or activity ofthe subject, the closed-loop therapy delivery system 10 canautomatically decrease or normalize abnormal sympathetic activity andthus effectively treat autonomic instability or a medical conditionassociated therewith.

Another aspect of the present disclosure can include transvascular ortransluminal delivery of an electrical energy to an autonomic nervoustissue target or spinal nervous tissue target associated with autonomicinstability or a medical condition associated therewith (e.g., aneurological or neurodegenerative disorder). Thus, in some instances,the method 20 can include providing a therapy delivery device (orsystem) configured for transvascular or transluminal insertion andplacement within the subject. For instance, a therapy delivery deviceconfigured for intravascular or intraluminal placement in a subject caninclude an expandable electrode as disclosed in the '331 application.The therapy delivery device can be inserted into a vessel or lumen ofthe subject. Non-limiting examples of vessel and lumens into which thetherapy delivery device can be inserted include arteries, veins, anesophagus, a trachea, a vagina, a rectum, or any other bodily orifice.The therapy delivery device can be surgically inserted into the vesselor lumen via a percutaneous, transvascular, laparoscopic, or opensurgical procedure.

After inserting the therapy delivery device into the vessel or lumen,the therapy delivery device can be advanced (if needed) to anintraluminal target site so that the therapy delivery device is inelectrical communication with the autonomic nervous tissue target orspinal nervous tissue target. In some instances, advancement of thetherapy delivery device can be done under image guidance (e.g.,fluoroscopy, CT, MRI, etc.). Intraluminal target sites can includeintravascular or intraluminal locations at which the therapy deliverydevice can be positioned. For example, an intraluminal target site caninclude a portion of a vessel wall that is innervated by (or inelectrical communication with) the autonomic nervous tissue target orspinal nervous tissue target. Examples of intraluminal target sites caninclude, without limitation, vascular or luminal sites innervated byand/or in electrical communication with any nervous tissue(s) of the SNSor PNS, such as neurons, axons, fibers, tracts, nerves, plexus, afferentplexus fibers, efferent plexus fibers, ganglion, pre-ganglionic fibers,post-ganglionic fibers, cervical sympathetic ganglia/ganglion, thoracicsympathetic ganglia/ganglion, afferents thereof, efferents thereof, asympathetic chain ganglion, a thoracic sympathetic chain ganglion, anupper cervical chain ganglion, a lower cervical ganglion, an inferiorcervical ganglion, and a stellate ganglion.

After placing the therapy delivery device, a therapy signal (e.g., anelectrical signal or a magnetic field) can be delivered to the autonomicnervous tissue target or spinal nervous tissue target. The therapysignal can be delivered in an amount and for a time sufficient toeffectively treat autonomic instability or a medical conditionassociated therewith.

In another aspect, the method 20 can include providing a therapydelivery device (or system) configured for placement on the skin of themammal. Examples of therapy delivery devices configured fortranscutaneous delivery of one or more therapy signals are disclosedabove and described in more detail below. In some instances, a therapydelivery device (or system) can be positioned about the subject, withoutpenetrating the skin of the subject, so that the therapy delivery deviceis in electrical communication with an autonomic nervous tissue targetor spinal nervous tissue target associated with autonomic instability ora medical condition associated therewith. Non-limiting examples of anautonomic nervous tissue target or spinal nervous tissue target intowhich the therapy delivery device can be placed into electricalcommunication are described above. After placing the therapy deliverydevice (or system), a therapy signal can be delivered to the autonomicnervous tissue target or spinal nervous tissue target. The therapysignal can be delivered in an amount and for a time sufficient toeffectively treat autonomic instability or a medical conditionassociated therewith.

In one example, a transcutaneous neuromodulation device can comprise awearable accessory item, such as a necklace or collar 30 (FIG. 6). Asshown in FIG. 6, a necklace or collar 30 can be configured to include atleast one electrode 32 for delivering a therapy signal to a particularregion of a subject's neck (e.g., an anterior or posterior regionthereof) depending upon the desired neuromodulatory effect. The necklaceor collar 30 can additionally include an integral power source 34 (e.g.,a rechargeable battery). It will be appreciated that the electrode(s) 32can alternatively be powered by a wireless power source (not shown). Thenecklace or collar 30 can be configured to obtain a pre-selectedposition about a subject's neck by, for example, using a positioningguide (not shown), weighting the necklace or collar, etc. Alternatively,the subject can manually adjust the necklace or collar 30 as needed tooptimize delivery of the therapy signal from the electrode(s) 32 to anautonomic nervous tissue target or spinal nervous tissue target.

In another example, a transcutaneous neuromodulation device can comprisea pillow 40 (FIGS. 7A-B). In some instances, the pillow 40 (FIG. 7A) canbe configured as a collar for use in a reclined or upright position,such as on an airplane, in a car, on a couch, etc. The pillow 40 caninclude at least one electrode 42 configured to deliver a therapy signalto an autonomic nervous tissue target or spinal nervous tissue target(e.g., in a subject's head or neck). As shown in FIG. 7A, the pillow 40includes two oppositely disposed electrodes 42. The pillow 40 can alsoinclude a power source (not shown), which may be integrally connectedwith the pillow or located remotely (i.e., wirelessly) therefrom. Inother instances, the pillow 40 (FIG. 7B) can comprise a traditional orconventional pillow for use when a subject is sleeping or lying in bed.As shown in FIG. 7B, the pillow 40 can include two oppositely disposedelectrodes 42 configured to deliver a therapy signal to a target nervewhen the subject neck or head is straddled between the electrodes. Thepillow 40 can further include a power source 44 that is in directelectrical communication with the electrodes 42; however, it will beappreciated that the power source can be located remotely (i.e.,wirelessly) from the pillow.

It will be appreciated that the transcutaneous neuromodulation devicesillustrated in FIGS. 6 and 7A-B are illustrative only and, moreover,that such devices can include any wearable item, accessory, article ofclothing, or any object, device, or apparatus that a subject can useand, during use, comes into close or direct contact with a portion ofthe subject's body (e.g., the subject's neck). Examples of suchtranscutaneous neuromodulation devices can include vests, sleeves,shirts, socks, shoes, underwear, belts, scarves, wrist bands, gloves,ear pieces, band-aids, turtle neck, pendants, buttons, earrings,stickers, patches, bio-films, skin tattoos (e.g., using neuro-paint),chairs, computers, beds, head rests (e.g., of a chair or car seat), cellphones, and the like.

Another example of the method 20 is illustrated in FIG. 8. At Step 22,the method 20 can include providing a closed-loop therapy system 10 asdescribed above. The closed-loop therapy system 10 can be configured forpercutaneous (e.g., subcutaneous) implantation in the subject. As shownin FIG. 8, the system 10 can be implanted in the subject so that thedelivery component 14 and the sensing component 12 are in directelectrical contact with a spinal cord segment at the level of C8 and aspinal cord segment at the level of C6, respectively. Additionally, thesystem 10 can be implanted so that the controller 16 and the powersource 18 are secured at the same or different subcutaneous locations.

Once the system 10 is implanted (Step 24), the sensing component 12 candetect electrical activity in the C6 spinal cord segment, which may beindicative of intrinsic sympathetic tone in the subject. The detectedlevel(s) of electrical activity can then be relayed to the controller16, which determines if the detected level(s) is/are within a normal orabnormal range or level. Where the detected level(s) is/are within anabnormal range (e.g., at an elevated level as compared to a control orbaseline), the controller 16 can cause the power source 18 to deliver anelectrical signal to the delivery component 14. The electrical signal isthen delivered to the spinal cord segment at the level of C8 tosubstantially block activity therein (Step 26). While the electricalsignal(s) is/are being delivered to the spinal cord segment at the levelof C8, the sensing component 12 can continue to detect the level ofelectrical activity within the spinal cord segment at the level of C6(Step 28). When the level of electrical activity in the spinal cordsegment at the level of C6 is equal, or about equal to, a normal orbaseline level, the controller 16 can cease delivery of the electricalsignal(s) to the delivery component 14. By continuously orintermittently monitoring the intrinsic sympathetic tone or activity ofthe subject, the closed-loop therapy delivery system 10 canautomatically decrease or normalize hypersympathetic activity and thuseffectively treat autonomic instability or a medical conditionassociated therewith.

From the above description of the present disclosure, those skilled inthe art will perceive improvements, changes and modifications. Suchimprovements, changes, and modifications are within the skill of thosein the art and are intended to be covered by the appended claims. Allpatents, patent applications, and publication cited herein areincorporated by reference in their entirety.

1-22. (canceled)
 23. A closed-loop therapy delivery system for treatingautonomic instability or a medical condition associated therewith in asubject, the therapy delivery system comprising: a sensing componentconfigured to detect at least one physiological parameter associatedwith autonomic instability or the medical condition associatedtherewith; a delivery component configured for implantation on or aboutan autonomic nervous tissue target or a spinal nervous tissue target;and a controller configured to automatically coordinate operation of thesensing and delivery components; wherein the controller is programmed todeliver an electrical signal to the delivery component to modulateactivity at the autonomic nervous tissue target or a spinal nervoustissue target and effectively treat the autonomic instability or themedical condition associated therewith.
 24. The system of claim 23,wherein the controller is programmed to deliver an electrical signalthat substantially blocks activity at the autonomic nervous tissuetarget or a spinal nervous tissue target.
 25. The system of claim 24,wherein the controller is programmed to deliver an electrical signalhaving a frequency of about 10,000 Hz to about 25,000 Hz.
 26. The systemof claim 23, wherein the controller is programmed to deliver anelectrical signal that substantially increases sympathetic activity atthe autonomic nervous tissue target or a spinal nervous tissue target.27. The system of claim 23, wherein the at least one physiologicalparameter includes a chemical moiety or an electrical activity.
 28. Thesystem of claim 23, wherein the autonomic nervous tissue target is aganglion of the sympathetic nervous system (SNS).
 29. The system ofclaim 28, wherein the ganglion of the SNS is a cervical ganglion, acervicothoracic ganglion, or a thoracic ganglion.
 30. The system ofclaim 29, wherein the cervical ganglion is an upper, middle, or lowercervical ganglion.
 31. The system of claim 23, wherein the spinalnervous tissue target is one of a cervical spinal cord segment, athoracic spinal cord segment, a lumbar spinal cord segment, a sacralspinal cord segment, or spinal nervous tissue associated therewith. 32.A method for treating autonomic instability or a medical conditionassociated therewith in a subject, the method comprising the steps of:placing a therapy delivery device into electrical communication with anautonomic nervous tissue target or a spinal nervous tissue targetassociated with autonomic instability or the medical conditionassociated therewith; and activating the therapy delivery device todeliver an electrical signal to the autonomic nervous tissue target or aspinal nervous tissue target to effectively treat autonomic instabilityor the medical condition associated therewith in the subject.
 33. Themethod of claim 32, further comprising the steps of: sensing at leastone physiological parameter associated with autonomic instability or themedical condition associated therewith; generating a sensor signal basedon the at least one physiological parameter; and activating the therapydelivery device to adjust application of the electrical signal to theautonomic nervous tissue target or a spinal nervous tissue target inresponse to the sensor signal to treat autonomic instability or themedical condition associated therewith.
 34. The method of claim 32,wherein the therapy delivery device is programmed to deliver anelectrical signal that substantially increases sympathetic activity atthe autonomic nervous tissue target or a spinal nervous tissue target.35. The method of claim 32, wherein the therapy delivery device isprogrammed to deliver an electrical signal that substantially decreasessympathetic activity at the autonomic nervous tissue target or a spinalnervous tissue target.
 36. The method of claim 35, wherein theelectrical signal has a frequency of about 10,000 Hz to about 25,000 Hz.37. The method of claim 33, wherein the at least one physiologicalparameter includes a chemical moiety or an electrical activity.
 38. Themethod of claim 32, wherein the autonomic nervous tissue target is aganglion of the SNS.
 39. The method of claim 38, wherein the ganglion ofthe SNS is a cervical ganglion, a cervicothoracic ganglion, or athoracic ganglion.
 40. The method of claim 39, wherein the cervicalganglion is an upper, middle, or lower cervical ganglion.
 41. The methodof claim 32, wherein the spinal nervous tissue target is one of acervical spinal cord segment, a thoracic spinal cord segment, a lumbarspinal cord segment, a sacral spinal cord segment, or spinal nervoustissue associated therewith.
 42. The method of claim 32, wherein themedical condition associated with autonomic instability is aneurological condition.